Implication of geranylgeranyltransferase I in synapse formation

Neuron. 2003 Nov 13;40(4):703-17. doi: 10.1016/s0896-6273(03)00695-0.

Abstract

Agrin activates the transmembrane tyrosine kinase MuSK to mediate acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ). However, the intracellular signaling mechanism downstream of MuSK is poorly characterized. This study provides evidence that geranylgeranyltransferase I (GGT) is an important signaling component in the Agrin/MuSK pathway. Agrin causes a rapid increase in tyrosine phosphorylation of the alpha(G/F) subunit of GGT and in GGT activity. Inhibition of GGT activity or expression prevents muscle cells from forming AChR clusters in response to Agrin and attenuates the formation of neuromuscular synapses in spinal neuron-muscle cocultures. Importantly, transgenic mice expressing an alpha(G/F) mutant demonstrate NMJ defects with wider endplate bands and smaller AChR plaques. These results support the notion that prenylation is necessary for AChR clustering and the NMJ formation and/or maintenance, revealing an active role of GGT in Agrin/MuSK signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agrin / metabolism*
  • Agrin / pharmacology
  • Alkyl and Aryl Transferases / antagonists & inhibitors
  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism*
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Neuromuscular Junction / cytology
  • Neuromuscular Junction / enzymology*
  • Neuromuscular Junction / growth & development*
  • Organ Culture Techniques
  • Peptides / pharmacology
  • Phosphorylation
  • Protein Prenylation / physiology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cholinergic / genetics
  • Receptors, Cholinergic / metabolism*
  • Receptors, Nicotinic / metabolism
  • Synaptic Membranes / enzymology*
  • Synaptic Membranes / genetics
  • Tyrosine / metabolism
  • Xenopus laevis
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / metabolism

Substances

  • Agrin
  • Enzyme Inhibitors
  • Peptides
  • Protein Subunits
  • Receptors, Cholinergic
  • Receptors, Nicotinic
  • Tyrosine
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • MuSK protein, rat
  • Receptor Protein-Tyrosine Kinases
  • rho GTP-Binding Proteins